Tyrosine kinase inhibitor (TKIs) are used in cancer treatment because they are orally active, highly potent, and have good profile with respect to adverse reactions. Epidermal growth factor receptor (EGFR) is a cell surface transmembrane protein that belongs to a family of receptor tyrosine kinases. Binding by its specific ligand epidermal growth factor (EGF) will activate EGFR intrinsic protein-tyrosine kinase activity to initiate the EGFR signaling cascade. EGFR signaling is critical to normal embryogenesis, cell cycle progression, organ development and human physiology. Aberrant EGFR signaling has been associated with various diseases including cancers. EGFR functional domain mutations leading to increased EGFR activities have been recognized as oncogenic drivers and found in cancers such as non-small-cell lung cancer, metastatic colorectal cancer, gluoblastoma, head and neck cancer, pancreatic cancer and breast cancer. Therefore, targeting EGFR activities has been a major focus in cancer therapy.
NSCLC is the most common type of lung cancer, making up 85% of all lung cancers. It is the leading cause of cancer-related death worldwide, with a 5-year predicted survival rate of 16%. NSCLC can be divided into three subtypes based on their pathological characteristics: adenocarcinoma (ADC, 40%), squamous cell carcinoma (SCC, 30%), and large cell carcinoma (LCC, 15%).
Recent advances in next generation sequencing (NGS) and high-throughput genomic profiling of tumors from NSCLC patients have uncovered over twelve oncogenic drivers, further defining NSCLC as a group of distinct diseases with genetic and cellular heterogeneity. Those oncogenic drivers have become potential therapeutic targets. The development of precision molecular target agents has radically changed the therapeutic landscape for treating NSCLC. Mutations in Kras, BRAF and EGFR were most prominent in patients with adenocarcinoma. EGFR mutations occur in about 30% to 40% ADC in Asian patients and in about 15% in Western patients. First generation EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib have been used in treatment of EGFR-mutated advanced NSCLC patients with L858R/Del19 and have achieved higher objective response rate, longer progression-free survival and better tolerability, and therefore represent the best therapeutic option in first-line, second-line and maintenance setting for EGFR mutant patients. Unfortunately, virtually all patients develop acquired resistance after nine- to twelve-month treatment, despite an initial benefit. The molecular mechanisms responsible for acquired resistance have been attributed to the up-regulation of the downstream signal by mesenchymal-epidermal transition (MET) amplification and the emergence of recurrent secondary T790M EGFR gatekeeper mutation (60%). Osimertinib (AZD9291) was designed to irreversibly inhibit EGFR-T790M kinase activity, and was developed as an orally active, second-line therapy for patients who develop EGFR-T790M resistant mutation after treatment with first-line EGFR TKIs.
However, over 20% patients treated with Osimertinib will develop adverse reactions, including severe drug-induced toxicities such as high fever, pneumonia and hepatotoxicity. There is an urgent and unmet medical need for innovative cancer therapeutics and treatment methods that can overcome acquired resistance, leading to improved clinical effectiveness with reduced side effects. To this end, structural modification of existing drugs has been playing a significant role in generating new chemical entities that are biologically potent and physiologically active with improved pharmacokinetic, therapeutic, and toxicological profiles.
One such methodology is by fluorine substitution. Over the last twenty years, many fluorinated compounds have been synthesized routinely in pharmaceutical research for generating new drug candidates, including anti-cancer agents. (Shah, et al. 2007 Journal of Enzyme Inhibition and Medicinal Chemistry 22(5):527-40.) The size of a fluorine atom (1.4 Å) is comparable to that of a hydrogen atom (1.20 Å), making it possible for the former to replace the latter at a strategically important position. The advantages of a fluorine-substituted compound include higher electron-withdrawing property, greater C—F bond stability over C—H bond, superior lipophilicity, etc. Therefore, fluorination may improve a drug's metabolic stability alter its physicochemical properties, increase its protein-binding affinity, etc.
Another such methodology is to use deuteration as a tool for the optimization of metabolic stability and/or toxicity of drugs. (Suldminder and Monika 2017 Glob J Pharmaceu Sci. 1(4): 555566). A primary kinetic isotope effect may be found when a bond to the isotopically labeled atom is being formed or broken. Thus, a demented drug may have a longer half-life than the hydrogen version. This could result in a lower dosage and thus a safer treatment.